Accumulating clinical evidence shows that many of the drugs of abuse (including cocaine) have vasoactive effects that may result in cerebrovascular pathology and cerebral blood flow (CBF) dysfunction such as aneurysm-like bleeds, hemorrhagic and ischemic strokes. The mechanisms underlying cocaine's neurovascular toxicity remain ambiguous, and as a result effective treatment may be hindered by difficulties in assessing the nature and severity of vasoactive effects of cocaine. This key knowledge gap is due in part to the limitations of current neuroimaging techniques (i.e., lack of either high spatiotemporal resolution or sufficient field of view for imaging capillary CBF networks) used to investigate cocaine-induced vascular effects in animal models. In this R21 CEBRA grant, we propose to bridge the gap by developing a novel neuroimaging technique based on ultrahigh-resolution optical coherence Doppler tomography, which enables quantitative 3D imaging of capillary CBF networks and allows one to assess real-time functional changes in vivo. Results from our preliminary animal studies have shown the capabilities of this imaging technique to accurately detect laser-induced micro-vessel rupture and the consequent CBF disruption, as well as to quantify 3D CBF network changes (including capillary CBF) in response to hypercapnia, all of which have laid a solid foundation for the proposed technological development and animal validation study. Our new strategy in this application is to combine ultrahigh-resolution 3D optical angiography and Doppler tomography to investigate cocaine- induced neurovascular pathology (micro hemorrhage) and hemodynamic dysfunction (including capillary CBF changes). The following Specific Aims are proposed: (1) develop and optimize ultrahigh-resolution laser Doppler tomography to enable in vivo quantitative 3D imaging of capillary CBF networks, (2) validate this new technique for real-time imaging assessment of cocaine-induced neurovascular toxicity using a well-established rat model of compulsive cocaine use. Successful development and validation of this new technique will permit label-free, quantitative 3D imaging of capillary CBF networks and their real-time responses to cocaine at high spatial and temporal resolution (<35m, ~30s), which will permit an in vivo assessment of potential toxic effects of cocaine to micro vessels and concomitant impairment to the microcirculation that would be undetected by other technologies. Such a technology, in addition to providing new insights into the mechanisms underlying cocaine's cerebrovascular toxicity, will also be valuable to evaluate medications to help recover from cerebrovascular toxicity of cocaine and other cerebrovascular pathologies. PUBLIC HEALTH RELEVANCE: Label-free, quantitative imaging of cerebral blood flow (CBF) at high temporal and spatial resolution would improve our ability to investigate the mechanisms underlying drug induced neurovascular toxicity (including cocaine) as well as that of other cerebrovascular diseases. Based on ultrahigh-resolution optical coherence Doppler tomography, this R21 CEBRA proposal seeks to develop a novel neuroimaging technique, which for the first time permits quantitative imaging of 3D capillary CBF networks and their changes at high spatiotemporal resolutions across a large field of view. In addition, we will test its efficacy for assessing cocaine-induced neurovascular pathology (micro-vessel rapture) and hemodynamic dysfunction (including capillary CBF changes) in vivo. The outcomes from this proposal will provide with better tools to image dynamic vascular changes that occur with chronic drug exposures and hence a tool with which to test potential medications to reverse neurovascular pathology. From its application into assessing the effects of chronic cocaine we also expect to gain with new insights into the neurovascular pathology resulting from chronic cocaine exposure.